IRUS Total

The structure-function relationship of oncogenic LMTK3.

File Description SizeFormat 
eabc3099.full.pdfPublished version10.32 MBAdobe PDFView/Open
Title: The structure-function relationship of oncogenic LMTK3.
Authors: Ditsiou, A
Cilibrasi, C
Simigdala, N
Papakyriakou, A
Milton-Harris, L
Vella, V
Nettleship, JE
Lo, JH
Soni, S
Smbatyan, G
Ntavelou, P
Gagliano, T
Iachini, MC
Khurshid, S
Simon, T
Zhou, L
Hassell-Hart, S
Carter, P
Pearl, LH
Owen, RL
Owens, RJ
Roe, SM
Chayen, NE
Lenz, H-J
Spencer, J
Prodromou, C
Klinakis, A
Stebbing, J
Giamas, G
Item Type: Journal Article
Abstract: Elucidating signaling driven by lemur tyrosine kinase 3 (LMTK3) could help drug development. Here, we solve the crystal structure of LMTK3 kinase domain to 2.1Å resolution, determine its consensus motif and phosphoproteome, unveiling in vitro and in vivo LMTK3 substrates. Via high-throughput homogeneous time-resolved fluorescence screen coupled with biochemical, cellular, and biophysical assays, we identify a potent LMTK3 small-molecule inhibitor (C28). Functional and mechanistic studies reveal LMTK3 is a heat shock protein 90 (HSP90) client protein, requiring HSP90 for folding and stability, while C28 promotes proteasome-mediated degradation of LMTK3. Pharmacologic inhibition of LMTK3 decreases proliferation of cancer cell lines in the NCI-60 panel, with a concomitant increase in apoptosis in breast cancer cells, recapitulating effects of LMTK3 gene silencing. Furthermore, LMTK3 inhibition reduces growth of xenograft and transgenic breast cancer mouse models without displaying systemic toxicity at effective doses. Our data reinforce LMTK3 as a druggable target for cancer therapy.
Issue Date: Nov-2020
Date of Acceptance: 30-Sep-2020
URI: http://hdl.handle.net/10044/1/84171
DOI: 10.1126/sciadv.abc3099
Journal / Book Title: Sci Adv
Volume: 6
Issue: 46
Copyright Statement: Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S.Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).
Sponsor/Funder: National Institute for Health Research
Imperial College Healthcare NHS Trust- BRC Funding
Funder's Grant Number: NIHR-RP-011-053
RDB01 79560
Publication Status: Published online
Conference Place: United States
Appears in Collections:Department of Metabolism, Digestion and Reproduction
Department of Surgery and Cancer
Faculty of Natural Sciences

This item is licensed under a Creative Commons License Creative Commons